Santa Clara Valley Medical Center

Aspergillus species have emerged as an important cause of life-threatening infections in immunocompromised patients. This expanding population is composed of patients with prolonged neutropenia, advanced HIV infection, and inherited immunodeficiency and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) and/or lung transplantation. This document constitutes the guidelines of the Infectious Diseases Society of America for treatment of aspergillosis and replaces the practice guidelines for Aspergillus published in 2000 The objective of these

No controlled trials of therapy for invasive aspergillosis have been done. This review appraises 2,121 cases reported in 497 articles in the literature and analyzes 440 courses of treatment of infection at various body sites in 379 patients. The exclusion of early failures of therapy skews the results toward a favorable outcome. The rate of response to amphotericin B is 55%. Mortality from pulmonary aspergillosis in bone marrow transplant recipients exceeds 94% regardless of therapy, as does that from cerebral aspergillosis in all hosts. Amphotericin B (1 mg/[kg.d]) with flucytosine lowers mortality in neutropenic patients with pulmonary aspergillosis who did not receive a bone marrow transplant; relapse is common. Surgical debridement of aspergillus maxillary sinusitis is usually curative in nonimmunocompromised patients, whereas it increases mortality among neutropenic patients. Valve replacement is essential for aspergillus endocarditis. Both vitrectomy and intravitreal amphotericin B treatment are essential for aspergillus endophthalmitis. Flucytosine is somewhat useful clinically. Itraconazole shows efficacy in the treatment of pulmonary, skeletal, and pericardial aspergillosis. Although liposomal amphotericin B is less toxic than standard preparations of the drug, relevant data are limited. The proposed potentiation of amphotericin B by rifampin is unsupported by clinical data. Despite "conventional" therapy, mortality from invasive aspergillosis remains high; new approaches must be investigated.

BACKGROUND: Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. OBJECTIVES: To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. SEARCH STRATEGY: A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. SELECTION CRITERIA: Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. DATA COLLECTION AND ANALYSIS: The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. MAIN RESULTS: Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. AUTHORS' CONCLUSIONS: There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1–1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be ∼0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). Although the frequency of these diseases is on the rise, there is a paucity of randomized comparative trials involving these entities; therefore, the recommendations represent a compromise and consensus among students of these diseases (i.e., the authors). They have synthesized the recommendations from published and personal experience, including case series, open trials, and any comparative trials, as indicated. Aspergillus species are saprophytic molds found worldwide. Diseases caused by Aspergillus species are most commonly caused by Aspergillus fumigatus, with Aspergillus flavus the second most frequently isolated pathogen. Other species reported to cause disease include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus candidus, Aspergillus carneus, Aspergillus caesiellus, Aspergillus clavatus, Aspergillus glaucus, Aspergillus granulosus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Aspergillus quadrilineatus, Aspergillus restrictus, Aspergillus sydowi, Aspergillus terreus, Aspergillus ustus, and Aspergillus versicolor. The frequency and relative importance of these infections are on the rise in all developed countries, which is possibly related to increased numbers of immunocompromised patients, owing to improved survival from AIDS, malignancies and more intensive cytotoxic therapy, more transplantation (with immunosuppression) for organ dysfunctions, and better therapy and prophylaxis for candidal infections. These guidelines are drafted to ensure appropriate and successful therapy for 3 main diseases caused by Aspergillus species. They include invasive aspergillosis, ABPA, and aspergilloma. The guidelines proposed initially are general and are followed by modifications for individual clinical settings. The guidelines are based on scientific publications and peer-reviewed information (this documentation is provided), and are largely concerned with therapy. The guidelines are not intended to be a comprehensive treatise on pathogenesis or diagnosis. The categories of ranking of the strength of the recommendation and the quality of the evidence are given in tables 1 and 2. Guidelines for prophylaxis and empirical therapy for invasive aspergillosis in neutropenic hosts have recently been published [1] and will not be discussed here. Categories reflecting the strength of each recommendation for or against the use of therapy for diseases caused by Aspergillus species. Categories indicating the quality of evidence for recommendations for antifungal therapy in diseases caused by Aspergillus species. General and specific commentary on antifungal drugs has been provided in a previous guideline in this series. The drugs available to treat aspergillosis presently include amphotericin B in deoxycholate [2–4], a familiar drug with 40 years' clinical experience; 3 lipid-based preparations of amphotericin B [5–12]; and itraconazole, an oral and iv triazole [13–18]. In general, the largest databases for therapy in aspergillosis concern amphotericin B deoxycholate and various surgical modalities. There is thus some concern about the efficacy of the newer in patients with rapidly invasive Itraconazole has drug which are in patients at of aspergillosis, because such patients are receiving other drugs for a variety of These patients also have as a of these therefore, oral itraconazole is serum should be to ensure adequate (BII). should be given to the oral of itraconazole in such patients, because is to that with itraconazole iv has been but there is information available about that any drug used for invasive disease be given at for 1–1.5 mg/kg/d of amphotericin B deoxycholate, mg/kg/d of formulations of and of itraconazole (BIII). in serum creatinine level with amphotericin B deoxycholate is and with amphotericin use are to the dose because of a modest of and have against Aspergillus species and are or clinical oral triazole and 3 and are also in of clinical Invasive aspergillosis is a that patients with or cytotoxic chemotherapy, corticosteroid therapy, or organ or or in patients at and prompt of antifungal therapy may be for patient survival (BIII). The are the most of invasive disease it in frequency in some The is the most of invasive most of the in this are on invasive pulmonary The of this disease and to therapy in to the and to to for clinical trials have and will to as clinical trials such as the of and Diseases the for and of and and to of previous trials and the and to a evidence of in and Aspergillus species from by from the from a and rarely Aspergillus species. The of Aspergillus are by and and it would be to include these in the initial invasive disease is Aspergillus are to from those of of and some other Aspergillus species from of the (e.g., and are a of in the but may invasive disease in the immunocompromised The may be as as in patients with or studies may include such as or on on include the of a lung initially by or an the the of a lung caused by of These studies may and the of in neutropenic patients, but the are not because other infections and may The have been in neutropenic commonly chest the more specific and chest should be considered in patients with a infection. resolution or may an with of the by has and for invasive aspergillosis in immunocompromised patients (BII). or are (CIII). of have been useful such are Because of the of the a definitive of disease caused by Aspergillus is The use of against Aspergillus to invasive aspergillosis has in are frequently or more isolated but specific recommendations about frequency of have not been have been developed to Aspergillus in and by and These more and with an available in for of Aspergillus reported of and of largely among in in some studies with that case to be has been in some studies with In some more among the and more in are for use in the In that use have been reported to the of Aspergillus species the in the of Aspergillus species and a in the of and may more of these have been with in trials of invasive aspergillosis, and must be There is also in such as or for of invasive are with some but not evidence of invasive pulmonary and treatment may need to be initiated at that in the more immunocompromised or to or the should in such an empirical treatment The optimal duration of therapy is and on the of invasive aspergillosis, the to therapy, and the underlying or course would be to therapy to treat clinical and are can be are and reversible underlying predispositions have (BIII). of therapy should be by clinical any of antifungal therapy chemotherapy, or of antifungal therapy in patients with who are about to chemotherapy, is of The of these patients to antifungal therapy is largely related to such as the resolution of and the of and the of function from a or organ as as the of aspergillosis Intravenous therapy may be at in patients who are because drug is certain (BIII). B has been the of treatment in invasive aspergillosis, for life-threatening and infections. In patients, the has been to all because of underlying of resolution of or underlying of duration of and other with in made in other a is more likely with in The lipid-based formulations are indicated for patients with invasive aspergillosis who nephrotoxicity while receiving amphotericin B (AII). The lipid-based preparations may be as initial therapy in patients with renal function or in patients receiving other The studies on the preparations have been or with amphotericin B comparative clinical trials amphotericin B and a specific lipid-based for invasive aspergillosis, or specific doses of to be or have been thus Although most studies have that doses of the preparations are to therapeutic to deoxycholate a has the doses are Itraconazole has been as therapy for invasive aspergillosis in studies which found of and These are of has been reported in may be among the immunocompromised The oral is an alternative to amphotericin in patients who are likely to to therapy, to have with and who are not receiving drugs that with itraconazole or which be and attractive would be to use iv therapy (e.g., amphotericin at disease is and with oral therapy for prolonged treatment (CIII). has been used in an of invasive aspergillosis with in studies has been that a triazole with any amphotericin B for invasive aspergillosis. therapy that amphotericin B with or has in and in has also been in and in has with limited in case but the of or efficacy of such has not been in invasive aspergillosis. In may in patients with and levels may be amphotericin is owing to the to function of the of may have significant drug owing to in who are receiving or and this also the of itraconazole use for Surgical has been successful for some of pulmonary prompt surgery as a for the the because of the of pulmonary such as such as or are for prophylaxis or therapy, in the neutropenic or immunocompromised host, but are not for therapeutic use (CIII). of increased survival has not been demonstrated with any of these modalities. to Aspergillus species at other are pulmonary and treatment trials are with most reported treatment In this the therapeutic recommendations are based on of or series, in to from the of infections at more such as lung infections. Aspergillus infections may or may not be invasive and can a or an course The disease manifestations and the subsequent treatment may also depending on the of of the invasive is the of aspergillosis that in the immunocompromised These infections are by with and of in to is from in patients with in who are therapy, to to in patients with or those transplantation of suspicion is in immunocompromised patients. Although are of or limited should be considered in these patients. is and the of new such as a in a host, or an should to including of the and subsequent of are not to but also to Aspergillus infections from those caused by other such as those to or species of by corticosteroid or resolution of the most that should with surgical (BIII). Although surgical alone may be in it may mortality among patients with surgery has been used for in which an is in an to with as as is more extensive surgery is indicated there is of the or or or is (BIII). amphotericin B or has been used by some invasive infections occur in hosts in with levels of such as the and other or and in patients with in other flavus is the most agent of these in to the of from of in immunocompromised These infections have a clinical course to with of the the and subsequent and with acute invasive infections in treatment of surgical and which is in the majority of (BIII). The of antifungal therapy is (CIII). this are Aspergillus infections may also as a or These to a for to with and no invasive surgical removal of the to ensure adequate antifungal therapy has no in these infections (CIII). The is Aspergillus species are a cause of allergic which in with a of allergic from is in of in the of the and is surgical with as for (BIII). antifungal therapy is not used there is evidence of or (CIII). corticosteroids and may be used for There may be a potential for corticosteroids with allergic in to surgery and in the there is a in corticosteroid use is because of corticosteroid of and of the and The of of Aspergillus of the have been reported in immunocompromised such as patients with or AIDS, organ or patients receiving chronic corticosteroid therapy that has commonly been limited to the has been in and lung or have been in patients who with and to this has rarely been reported antifungal therapy has been the of treatment in these Although amphotericin B may have a as therapy In the several reported of surgical or has been for a successful in to antifungal therapy. in the of Aspergillus with the of a in the removal of the by procedure may be given the of antifungals the infections. invasive and infections have been Aspergillus species may the in the with no infection. invasive of the has been in patients with and in patients with acute Aspergillus may Aspergillus In immunocompromised patients, antifungal therapy appears (BIII). infections of or those that occur in patients may be with including removal (BIII). variety of such therapeutic has been which amphotericin B and In these prolonged therapy may be infections. Aspergillus may occur by several including by surgical such as or by which is most commonly in immunocompromised patients, drug or patients with Aspergillus in these and of of amphotericin B and itraconazole the and is inadequate and treatment is Because of amphotericin B may be of in are that of serum experience with this agent in infections is may be for the and of these in with amphotericin B or amphotericin B (BIII). Other manifestations of Aspergillus infections are may be with surgery and amphotericin B it is not antifungal therapy is in these have been used for including the of with amphotericin B amphotericin B amphotericin B or Oral itraconazole may also a in these more since this agent the is there is while the patient is receiving therapy or there is a of Surgical include of a a to the from or or to or may be infections. Aspergillus infections of the may as or an or a The published that mortality in occur as a of with subsequent of and of these is to Aspergillus infections from those caused by other such as or which may of antifungal therapy has been reported to be in some surgical for of the agent with removal of which may not be by antifungals for have also been used Although surgery alone may be in the of in immunocompromised patients, antifungal therapy is also used in the majority of (BIII). in with amphotericin may have a because of There are of with itraconazole, or may be Aspergillus is are reported in drug or or patients on prolonged corticosteroid therapy. may as an of as a of therapy or in the surgery and rarely in patients with no underlying Aspergillus may be in the and may be used for of the course of therapy and (e.g., an amphotericin B has been used for the treatment of these infections as has itraconazole and of may be caused by Aspergillus are to a of such as in a Surgical with therapy is indicated for these infections (BIII). infections. The for Aspergillus infections is by by a surgical or in patients with the those with chronic or drug or is the most caused by Aspergillus with infections Surgical is for these infections. Although an case may be by surgical antifungal therapy is used in B levels in are which may the of drugs that have such as or Itraconazole and has also been used infections. infections caused by Aspergillus species are commonly a of from a of most the which in highly immunocompromised patients. These may be or may not be and occur most commonly on the They as and a with an that is by a Although this is of Aspergillus the is not and a with is indicated to other infections that may in a The majority of infections are caused by fumigatus, or terreus, more Aspergillus has been reported to cause which and in invasive infections to Aspergillus species have been reported in with for which are with Aspergillus These to of of may may also by Aspergillus species. may be caused by Aspergillus species. The of of for a definitive has been antifungal therapy is the of therapy and the are Surgical may be the be in the neutropenic In removal of the in to antifungal therapy is indicated aspergillosis and infections are by surgical in to therapy. Oral itraconazole, with or without therapy, such as is used for infections and Aspergillus species have been reported as a cause of and which is a of aspergillosis. The is rarely isolated from The are and and a of Because of the of amphotericin B the in to the of surgical with is in the of amphotericin B appears case has been with amphotericin B and alone is a of may from of a or from the with or of the may useful in diagnosis. of patients with or have been of antifungal therapy and including appropriate may be as an isolated or with infections. infections are a of that the renal are more in immunocompromised such as patients with or chronic or drug and patients with are at for infections that the renal The of a renal with or without a also occur antifungal therapy is used for of and surgical removal may be indicated. Therapy is by the in by itraconazole or or disease has been with amphotericin B or preparations the of may be since this agent in the with amphotericin B has also been used for and renal infections. infections. antifungal therapy is for aspergillosis The of this with amphotericin B therapy has been this amphotericin or itraconazole, of which in should be Aspergillus has as a of chronic removal is for these infections therapy should be used in and amphotericin B have been as has itraconazole organ with Aspergillus species most in the of infection. The is the most of in the the and in these may in or therapy is but the is infections. Aspergillus species may cause of In to antifungal therapy, surgical of the may be to the infection. aspergilloma. aspergilloma can be as a a pulmonary or of Aspergillus with and have underlying pulmonary disease such as sarcoidosis, or or lung disease The of aspergilloma is made without a lung and the chest are of importance in the diagnosis. pulmonary aspergilloma appears as a of a or and from the of the by an of and is The of an aspergilloma is made the are found in a patient with serum that are for an Aspergillus a with for aspergilloma some patients who corticosteroids may be Although aspergillomas are of as saprophytic of the lung with the manifestations of Aspergillus lung disease with a and Invasive pulmonary aspergillosis may from an aspergilloma and is chronic of Aspergillus has been in which symptoms (e.g., and are an aspergilloma is on chest radiograph, and evidence of is found on of lung is a of aspergilloma and may in is the cause of in to of patients with aspergilloma that aspergilloma on preventing life-threatening hemoptysis, patients with symptoms are candidates for therapy. have been that suggest a with aspergilloma. These include the of the underlying lung increasing or of aspergillomas on chest increasing Aspergillus-specific IgG titers underlying and Although not it that patients who have an of would be at of a life-threatening There is no consensus the treatment of aspergilloma. or randomized trials have been treatment have been from trials and case The decision in the of aspergilloma is therapy is Since life-threatening in a of patients, it may be to all patients with aspergilloma to therapy, since therapy is with significant morbidity and treatment for aspergilloma is surgical surgery has been with a morbidity and mortality is owing to the of and the of of the mortality is and such as and are that to the surgical of is that aspergillomas to in with pulmonary function in patients, surgery is because of underlying pulmonary has been that surgical of aspergilloma be to patients with and adequate pulmonary function and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). The course of the in the of surgery about surgical Bronchial artery embolization has been used to the that the in patients from aspergilloma other are in and can be is or and a patient who can for from the pulmonary and to the will not be successful should be considered as a temporizing procedure in a patient with life-threatening hemoptysis, who be for more definitive therapy the (BIII). for aspergillomas have therapy intracavitary or instillation of antifungal antifungals and antifungals symptoms (e.g., or are may be related in to with agent or to allergic has been in patients with evidence of (e.g., IgE and given corticosteroid therapy such therapy the of to invasive or disease of an infection. of these studies Intravenous amphotericin B for aspergilloma provided no pulmonary that used or intracavitary instillation of amphotericin B for aspergilloma of patients resolution or clinical is more in the patient with pulmonary The use of itraconazole for aspergilloma has been reported in several studies of these studies and not a the dose and duration of itraconazole therapy not the of these studies suggest that itraconazole may be in the treatment of aspergilloma (BIII). is a disease of the caused by initially as a disease by pulmonary and and or for ABPA proposed to Aspergillus to Aspergillus serum of pulmonary or and The of ABPA likely the and the of all made the certain of Aspergillus in by use of a of of or specific IgE directed against Aspergillus to Aspergillus and on with ABPA has been reported to be in of patients with in the patients with have with Aspergillus and ABPA these patients may be at for invasive aspergillosis lung transplantation is the chest in ABPA of that in the and may be These are commonly caused by with The with may a or a These are a of the disease and may be by a or may be on chest The of ABPA should be considered in a asthmatic or an asthmatic with any of the ABPA may clinical of acute to to lung disease with lung Therapy in ABPA is directed at acute asthmatic exacerbations and of Although corticosteroid therapy is the of therapy for ABPA, there is a paucity of data The studies of corticosteroids for ABPA have numbers of patients and have been nor and the corticosteroid dose has despite these data support the of corticosteroids in the of acute ABPA (AII). ABPA patients with mg/kg/d of for 1 followed by other made to The symptoms of and rapidly with this the dose of most patients developed symptoms of that with corticosteroids in most IgE levels with disease since with a clinical to corticosteroids and increased exacerbations of There have been studies that the treatment of chronic ABPA with and all have been ABPA patients for and found that patients a chronic course by pulmonary with in lung not a to as several asymptomatic patients developed and lung that in chronic lung doses in episodes of patients with pulmonary of ABPA patients given chronic corticosteroid therapy likely to those given These found that of for an to the of pulmonary the clinical course of patients with ABPA a of of with at a dose of There no significant in spirometry the These data are since pulmonary function not the a would be to the by a in a Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids are (BII). Multiple asthmatic exacerbations in an ABPA patient suggest that corticosteroid therapy should be at a dose of of (BIII). The decision to the of corticosteroids should be made on an individual basis, depending on the clinical course (BIII). to the treatment of ABPA is to Aspergillus species from the and oral are not in preventing In a Aspergillus-specific IgG and symptoms in ABPA patients. subsequent of an that not randomized no from trials have indicated that itraconazole is useful as therapy in ABPA, because the corticosteroid dose can be pulmonary function is and IgE levels recently for ABPA that itraconazole, for in significant in to as by the in corticosteroid dose and IgE and the in and in pulmonary Itraconazole may be useful as a agent (BII). corticosteroids not to be for ABPA some this may be a useful in some patients and suggest doses may be in to with exacerbations of ABPA there have been no studies of to ABPA, and the of such therapy therapy or of in the have not been

Because of the difficulties of recognizing allergic bronchopulmonary aspergillosis (ABPA) in the context of cystic fibrosis (because of overlapping clinical, radiographic, microbiologic, and immunologic features), advances in our understanding of the pathogenesis of allergic aspergillosis, new possibilities in therapy, and the need for agreed-upon definitions, an international consensus conference was convened. Areas addressed included fungal biology, immunopathogenesis, insights from animal models, diagnostic criteria, epidemiology, the use of new immunologic and genetic techniques in diagnosis, imaging modalities, pharmacology, and treatment approaches. Evidence from the existing literature was graded, and the consensus views were synthesized into this document and recirculated for affirmation. Virulence factors in Aspergillus that could aggravate these diseases, and particularly immunogenetic factors that could predispose persons to ABPA, were identified. New information has come from transgenic animals and recombinant fungal and host molecules. Diagnostic criteria that could provide a framework for monitoring were adopted, and helpful imaging features were identified. New possibilities in therapy produced plans for managing diverse clinical presentations.

Nonalcoholic fatty liver disease (NAFLD) is defined as the presence of hepatic fat accumulation after the exclusion of other causes of hepatic steatosis, including other causes of liver disease, excessive alcohol consumption, and other conditions that may lead to hepatic steatosis. NAFLD encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma (HCC). NAFLD is the most common liver disease in the world and NASH may soon become the most common indication for liver transplantation. Ongoing persistence of obesity with increasing rate of diabetes will increase the prevalence of NAFLD, and as this population ages, many will develop cirrhosis and end-stage liver disease. There has been a general increase in the prevalence of NAFLD, with Asia leading the rise, yet the United States is following closely behind with a rising prevalence from 15% in 2005 to 25% within 5 years. NAFLD is commonly associated with metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Our understanding of the pathophysiology of NAFLD is constantly evolving. Based on NAFLD subtypes, it has the potential to progress into advanced fibrosis, end-stage liver disease and HCC. The increasing prevalence of NAFLD with advanced fibrosis, is concerning because patients appear to experience higher liver-related and non-liver-related mortality than the general population. The increased morbidity and mortality, healthcare costs and declining health related quality of life associated with NAFLD makes it a formidable disease, and one that requires more in-depth analysis.

BACKGROUND: Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. RESULTS: Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. CONCLUSIONS: Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.

This review summarizes knowledge on various aspects of paracoccidioidomycosis. Mycelial propagules, chlamydospores, and arthroconidia exhibit thermal dimorphism; arthroconidia are infectious in animals and, by electron microscopy, appear well provided for survival. The mycelial-to-yeast-phase transformation requires a strict control of glucan synthesis probably mediated by membrane enzymes. Hormonal influences on the transformation of the fungus (mycelium or conidium to yeast phase) have been demonstrated. Estrogen-binding proteins have been detected in the fungal cytosol, and during the transformation novel proteins are produced as a result of estradiol incorporation. Clinical forms have been better defined on the basis of better experimental models. Emphasis has been placed on the lungs as the portal of entry and on the existence of silent pulmonary infections. A specific Paracoccidioides brasiliensis antigen, the 43-kDa glycoprotein (Gp43), has been identified, characterized, and cloned. This has led to improved reproducibility and specificity of serologic tests. The depression of cell-mediated immune responses has been associated with severe disease in humans and in the experimental host. T-cell subsets in patients' tissues were characterized by means of monoclonal antibodies, and a reduced CD4/CD8 ratio was demonstrated. This has been related to alterations in lymphokine and tumor necrosis factor production, production of antigen-antibody complexes, etc. Amphotericin B has provided effective therapy. Azole derivatives have also improved prognosis and facilitated therapy. Itraconazole is presently the drug of choice, yet incapacitating sequelae (mainly pulmonary fibrosis) still constitute major problems.

AIM: To quantify the effects of hormone-replacement therapy (HRT) on components of the metabolic syndrome in postmenopausal women. METHODS: Comprehensive searches of electronic databases were performed from April 1966 to October 2004. We included randomized controlled trials that were of at least 8 weeks duration and evaluated the effect of HRT on metabolic, inflammatory or thrombotic components. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Subgroup analysis evaluated the effects for transdermal and oral treatment and for diabetic and non-diabetic women. RESULTS: Pooled results of 107 trials showed that HRT reduced abdominal fat [-6.8% (CI, -11.8 to -1.9%)], HOMA-IR [-12.9% (CI, -17.1 to -8.6%)] and new-onset diabetes [relative risk 0.7 (CI, 0.6-0.9)] in women without diabetes. In women with diabetes, HRT reduced fasting glucose [-11.5% (CI, -18.0 to -5.1%)] and HOMA-IR [-35.8% (CI, -51.7 to -19.8%)]. HRT also reduced low-density lipoprotein/high-density lipoprotein cholesterol ratio [-15.7% (CI, -18.0 to -13.5%)], lipoprotein(a) [Lp(a)] [-25.0% [CI, -32.9 to -17.1%)], mean blood pressure [-1.7% (CI, -2.9 to -0.5%)], E-selectin [-17.3% (CI, -22.4 to -12.1%)], fibrinogen [-5.5% (CI, -7.8 to -3.2%)] and plasminogen activator inhibitor-1 [-25.1% (CI, -33.6 to -15.5%)]. Oral agents produced larger beneficial effects than transdermal agents, but increased C-reactive protein (CRP) [37.6% (CI, 17.4-61.3%)] and decreased protein S [-8.6% CI, -13.1 to -4.1%)], while transdermal agents had no effect. CONCLUSIONS: HRT reduces abdominal obesity, insulin resistance, new-onset diabetes, lipids, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes. Oral agents adversely affected CRP and protein S, while transdermal agents had no effects.

Seven patients developed chronic and severe parkinsonism after repeatedly injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously. Levodopa and bromocriptine controlled the symptoms; however, within months, five of the seven patients experienced dyskinesias or on-off fluctuations. Therefore, neither prolonged levodopa treatment nor progressive disease was necessary for on-off phenomena. Because the neurotoxic effects of MPTP seem limited to the substantia nigra, damage to this system alone may produce all the motor features of Parkinson's disease. MPTP differs from other neurotoxins in that it consistently produces a pure parkinsonian state.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which produces permanent parkinsonism in human and nonhuman primates. Treatment of squirrel monkeys with pargyline, a monoamine oxidase (MAO) inhibitor, prevents both clinical and neuropathological evidence of the neurotoxic effects of MPTP. Pargyline also inhibits conversion of MPTP to 1-methyl-4-phenylpyridinium ion (MPP+), a metabolic step that occurs rapidly after administration of MPTP in animals not treated with pargyline. It is proposed that the conversion of MPTP to MPP+, possibly involving MAO, may be important for the neurotoxic effects of MPTP to take place, and MPTP itself may not be the neurotoxic agent.

OBJECTIVE: To correlate self-reported antiretroviral adherence with virologic suppression. DESIGN: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. SETTING: Five university-affiliated HIV clinics. PATIENTS: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 x 10(6) cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. INTERVENTION: Individualized, unrestricted antiretroviral therapy. MEASUREMENTS: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. RESULTS: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log10 copies/ml increase in HIV RNA and a loss of 19 x 10(6) CD4 cells/l compared with a 1.1 log10 copies/ml decrease in HIV RNA and an increase of 72 x 10(6) CD4 cells/l in those reporting 100% adherence (P = 0.02). CONCLUSION: Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

BACKGROUND: Allergic bronchopulmonary aspergillosis is a hypersensitivity disorder that can progress from an acute phase to chronic disease. The main treatment is systemic corticosteroids, but data from uncontrolled studies suggest that itraconazole, an orally administered antifungal agent, may be an effective adjunctive therapy. METHODS: We conducted a randomized, double-blind trial of treatment with either 200 mg of itraconazole twice daily or placebo for 16 weeks in patients who met immunologic and pulmonary-function criteria for corticosteroid-dependent allergic bronchopulmonary aspergillosis. A response was defined as a reduction of at least 50 percent in the corticosteroid dose, a decrease of at least 25 percent in the serum IgE concentration, and one of the following: an improvement of at least 25 percent in exercise tolerance or pulmonary-function tests or resolution or absence of pulmonary infiltrates. In a second, open-label part of the trial, all the patients received 200 mg of itraconazole per day for 16 weeks. RESULTS: There were responses in 13 of 28 patients in the itraconazole group (46 percent), as compared with 5 of 27 patients in the placebo group (19 percent, P=0.04). The rate of adverse events was similar in the two groups. In the subsequent open-label phase, 12 of the 33 patients who had not had a response during the double-blind phase (36 percent) had responses, and none of the patients who had a response in the double-blind phase of the trial had a relapse. CONCLUSIONS: For patients with corticosteroid-dependent allergic bronchopulmonary aspergillosis, the addition of itraconazole can lead to improvement in the condition without added toxicity.

BACKGROUND: Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. METHODS AND FINDINGS: We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34-7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. CONCLUSION: TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.

At one time, the diagnosis of a deficiency of vitamin B12 or folate was considered to be relatively straightforward. As knowledge has accumulated, the limitations of such tests as serum vitamin level measurements and the Schilling test have become apparent. With the development of newer tests, atypical and subclinical deficiency states have been recognized. In this review, available tests used in the diagnosis of vitamin B12 and folate deficiency are discussed, and a rational approach to the diagnosis of these deficiency states is presented.

BACKGROUND AND METHODS: Symptomatic pulmonary aspergillosis has rarely been reported in patients with the acquired immunodeficiency syndrome (AIDS). We describe the predisposing factors, the clinical and radiologic features, and the therapeutic outcomes in 13 patients with pulmonary aspergillosis, all of whom had human immunodeficiency virus (HIV) infection and 12 of whom had AIDS. RESULTS: Pulmonary aspergillosis was detected a median of 25 months after the diagnosis of AIDS, usually following corticosteroid use, neutropenia, pneumonia due to other pathogens, marijuana smoking, or the use of broad-spectrum antibiotics. Two major patterns of disease were observed: invasive aspergillosis (in 10 patients) and obstructing bronchial aspergillosis (in 3). Cough and fever, the most common symptoms, tended to be insidious in onset in patients with invasive disease (median duration, 1.3 months before diagnosis). Breathlessness, cough, and chest pain predominated in the three patients with obstructing bronchial aspergillosis, who coughed up fungal casts. Radiologic patterns included upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies were usually negative, but positive cultures were obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Dissemination to other organs occurred in at least two patients, and direct invasion of extrapulmonary sites was seen in two others. The results of treatment with amphotericin B, itraconazole, or both were variable. Ten of the patients died a median of 3 months after the diagnosis (range, 0 to 12 months). CONCLUSIONS: Pulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully.

BACKGROUND: Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial. METHODS: A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy. RESULTS: Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms. CONCLUSIONS: Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia.

his document presents consensus panel recommendations for the medical care of pregnant women with preexisting diabetes, including type 1 and type 2 diabetes. The intent is to help clinicians deal with the broad spectrum of problems that arise in management of diabetes before and during pregnancy, and to prepare diabetic women for treatment that may reduce complications in the years after pregnancy. A thorough discussion of the evidence supporting the recommendations is presented in the book,

Methicillin-resistant Staphylococcus aureus, first identified just over 4 decades ago, has undergone rapid evolutionary changes and epidemiologic expansion. It has spread beyond the confines of health care facilities, emerging anew in the community, where it is rapidly becoming a dominant pathogen. This has led to an important change in the choice of antibiotics in the management of community-acquired infections and has also led to the development of novel antimicrobials.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.